B-type natriuretic peptide (BNP): can it improve our management of patients with congestive heart failure?

Minireview Peer reviewed article SWISS MED WKLY 2002;132:618 622 www.smw.ch 618 B-type natriuretic peptide (BNP): can it improve our management of patients with congestive heart failure? Christian Mueller, Peter Buser University Hospital Basel Summary Until recently no simple specific test existed for the differentiation of decompensated heart failure from other causes of acute dyspnoea, or to assess the prognosis of patients with severe heart failure or to optimize heart failure therapy in an individual patient. Measurement of B-type natriuretic peptide has become available as an easy-to-perform bedside test. Several studies have demonstrated it s usefulness in the emergency room to differentiate heart failure from other causes of acute dyspnoea or to guide the complex drug therapy in an individual patient with heart failure. This article gives a short overview on the clinical experience to use BNP-blood levels for the diagnosis and treatment guidance of heart failure. Key words: BNP; heart failure; diagnosis; treatment Introduction No financial support declared. The epidemic of heart failure (HF) is characterised by a steadily increasing incidence and prevalence and several studies predict a further increase over the next decades. This is due to demographic changes, ie, a larger proportion of elderly people, the higher prevalence of HF with increasing age, and an improved survival in patients with coronary artery disease [1]. However, the diagnosis of HF remained over all unchanged and is based on clinical history, physical examination, ECG, chest x-ray, and assessment of left ventricular function. For the first time since the introduction of echocardiography some 20 years ago, a simple blood test appears to offer a significant advance in this area. B-type natriuretic peptide (BNP) is a 32- amino acid polypeptide secreted from the cardiac ventricles (figure 1) in response to ventricular volume expansion and pressure overload [2, 3]. BNP levels are elevated in patients with left ventricular dysfunction, and levels correlate with severity of symptoms and with prognosis. Numerous studies [3 38] including the paper by Kuster et al. [38] in this issue indicate that BNP does have the potential to considerably improve our management of patients with HF failure and may become a routinely assessed serum parameter in clinical medicine. In this review we will discuss the utility of BNP in different clinical situations of HF with specific focus on the differential diagnosis of dyspnoea and the optimisation of therapy. Figure 1 BNP is produced from the cardiac myocytes as a prepro hormone of 134 amino acids, which is clipped into a probnp hormone. Upon stimulus for secretion, it is released into the blood as the fragment protein N-terminal probnp and the BNP molecule itself. The N-terminal portion is made of 77 amino acids and is a biologically inactive protein. BNP holds the biological activity. preprobnp (134 aa) probnp (108 aa) signal peptide (26 aa) secretion NT-proBNP (1 76) BNP (77 108) myocyte

SWISS MED WKLY 2002;132:618 622 www.smw.ch 619 Figure 2 Patients with congestive heart failure (CHF) do have significantly higher BNP levels as compared with patients with dyspnoea due to chronic obstructive lung disease (COPD) [16]. Figure 3 Correlation between the clinical severity of heart failure and BNP levels in the Breathing Not Properly (BNP) Multinational Study [19]. Diagnosis of dyspnoea Acute dyspnoea is a common symptom in patients presenting in the emergency department. Heart failure and primary lung disorders account for the majority of cases. In general, a careful history and physical examination, often completed with laboratory tests for inflammation (pneumonia) and chest X-ray, have a good diagnostic yield. However, in some circumstances, particularly in the elderly and/or obese patients, and in the presence of primary lung disorders, early diagnosis of decompensated HF may be difficult yet critical to determine the most effective management [2, 3]. Atypical presentation, language barriers, comorbidity, the busy and often noisy atmosphere in the emergency room, difficulty in evaluating the acute breathless and the low diagnostic yield of chest X- ray in this situation render the correct diagnosis of decompensated HF a real challenge. Numerous studies have shown that BNP levels are elevated in patients with left ventricular dysfunction [4 12]. In addition, BNP is significantly higher in patients with HF as the cause of acute dyspnoea as compared with patients whose dyspnoea is due to lung disease [13 19, 37]. Dao et al. [16] used the newly available point-of-care rapid assay for BNP (Triage Assay, Biosite Inc) in 250 patients presenting to the San Diego VA Healthcare Urgent Care Center. Patients diagnosed with HF (n = 97) had a significantly higher mean BNP concentration than the non-hf group (n = 139, 1076 ± 138 vs. 38 ± 4 pg/ml, figure 2). BNP at a cut off point of 80 pg/ml was found to be highly sensitive and highly specific for the diagnosis of HF. The negative predictive value of BNP concentrations under 80 pg/ml was 98% for the diagnosis of HF. Multivariate analysis revealed that BNP pg/ml 1200 1000 800 600 400 200 0 86 ± 39 COPD cause of dyspnea 1076 ±138 CHF median no HF NYHA I NYHA II NYHA III NYHA IV 50 150 250 550 900 (pg/ml) a BNP added significant diagnostic information after all useful diagnostic tools in the emergency department were taken into account. These results lead the FDA to approve the routine use of BNP for the differential diagnosis of acute dyspnoea in the emergency room. Moreover, the European Society of Cardiology Task Force for the Diagnosis and Treatment of Chronic heart Failure recently recommended the use of natriuretic peptides in the initial evaluation of patients with suspected HF [20]. The pilot studies mentioned above set the stage for a recently reported multicenter study [19, 37]. The Breathing Not Properly Multinational Study was a prospective diagnostic test evaluation study conducted in 7 centers. Of 1586 participants who presented with acute dyspnoea, 1538 (97%) had clinical certainty of HF determined by the attending physician in the emergency department. Participants underwent routine care and had BNP measured in a blinded fashion. The reference standard for HF was adjudicated by 2 independent cardiologists, also blinded to BNP results. The final diagnosis was HF in 722 participants (47%). At an 80% cut-off level of certainty for HF, clinical judgement had a sensitivity of 49% and specificity of 96%. At 100 pg/ml, BNP had a sensitivity of 90% and specificity of 73%. In determining the correct diagnosis (HF versus no HF), adding BNP to clinical judgement would have enhanced diagnostic accuracy from 74% to 81%. In those participants with an intermediate (21% to 79%) probability of HF, BNP at a cut-off of 100 pg/ml correctly classified 74% of the cases (figure 3). The areas under the receiver operating characteristic curve were 0.86, 0.90, and 0.93 for clinical judgement, for BNP at a cut-off of 100 pg/ml, and for the 2 in combination, respectively (p <0.0001 for all pairwise comparisons). These data led the authors to conclude that evaluation of acute dyspnoea would be improved with the addition of BNP testing to clinical judgement in the emergency department. However, it is important to note that there is still a lack of prospective data from randomised clinical trials establishing that a team in the emergency performs better with the use of this promising marker. One such trial randomising more than 400 patients has recently been completed at the University hospital of Basel. The final results of this and future trials will help define the role of BNP in this clinical setting. In our own institution, we have found that the negative predictive value of BNP levels under 100 pg/ml is the strongest feature of this peptide. Although the positive predictive value in a given patient at a cut-off of 100 pg/ml is 80%, most patients with significant HF as a cause of their dyspnoea will have levels of >500 pg/ml, particularly with dyspnoea present at rest at the time of

B-type natriuretic peptide (BNP): can it improve our management of patients with congestive heart failure? 620 (or the hour preceding) venipuncture. Patients with pulmonary oedema often have a BNP >1000 pg/ ml. Thus, in patients presenting with levels between 100 and 500 pg/ml, one may need to exclude baseline LV dysfunction without systolic HF, pulmonary embolism, and cor pulmonale. Prognosis in HF The assessment of an individual heart failure patient s prognosis is difficult. In patients with HF, there is a strong correlation between BNP and left ventricular end-diastolic pressure. Therefore, it is not surprising that BNP has been shown to be a powerful marker for prognosis and risk stratification in the setting of heart failure [21 31, 38]. Very high BNP levels, particular if unresponsive to medical therapy, herald a dismal prognosis. Prognosis in primary pulmonary hypertension In disorders primarily affecting the right ventricle, such as primary pulmonary hypertension (PPH), a strong correlation between BNP levels, the extent of volume and pressure overload (mean pulmonary artery pressure [32 34]) and prognosis has been reported. PPH patients with a BNP <180 pg/ml had a cumulative survival rate of 90% at 2-years as compared with only 20% in those with BNP >180 pg/ml [33]. Optimisation of therapy in HF As a low BNP level at discharge is associated with a favourable prognosis, maximal suppression of BNP-levels may be a reasonable goal of medical therapy. This concept has been tested in two randomised trials [35, 36]. Because BNP is a volumesensitive hormone with a short half-life (18 to 22 minutes), there may be a future for BNP levels in guiding diuretic and vasodilator therapy on presentation with decompensated HF. Most patients with chronic heart failure (HF) receive the same dose of angiotensin-converting enzyme (ACE) inhibitors because there is currently no measure of treatment efficacy. Murdoch et al. [35] sought to determine whether titration of vasodilator therapy according to plasma brain natriuretic peptide (BNP) concentration may be of value in the individual optimisation of vasodilator therapy in HF. Twenty patients with mild to moderate HF receiving stable conventional therapy including an ACE inhibitor were randomly assigned to titration of ACE inhibitor dosage according to serial measurement of plasma BNP concentration (BNP group) or optimal empirical ACE inhibitor therapy (clinical group) for 8 weeks. Only the BNP-driven approach was associated with significant reductions in plasma BNP concentration throughout the duration of the study and a significantly greater suppression when compared with empiric therapy after 4 weeks ( 42% vs 12%, p = 0.03). Both treatment strategies were well tolerated and associated with favourable neurohormonal and haemodynamic effects; however, in comparison between groups, mean heart rate fell (p = 0.02) and plasma renin activity rose (p = 0.03) in the BNP group when compared with the clinical group. Whether the concept of pharmacotherapy BNP guided would produce a superior outcome to empirical trial-based therapy dictated by clinical judgement was tested in the second study. Troughton et al. [36] randomised 69 patients with impaired systolic function (left-ventricular ejection fraction <40%) and symptomatic HF (NYHA class II IV) to receive treatment guided by either plasma NT-proBNP concentration (BNP group) or standardised clinical assessment (clinical group). During follow-up (median 10 months), there were fewer total cardiovascular events (death, hospital admission, or heart failure decompensation) in the BNP group than in the clinical group (19 vs 54, p = 0.02). At 6 months, 27% of patients in the BNP group and 53% in the clinical group had experienced a first cardiovascular event (p = 0.03). Changes in left-ventricular function, quality of life, renal function, and adverse events were similar in both groups. The authors concluded that NT-proBNP-guided treatment of HF reduced total cardiovascular events, and delayed time to first event compared with intensive clinically guided treatment. Readmission after hospitalisation for heart failure is surprisingly common, estimated at 40 50% at 6 months in Europe and the United States. Considering that hospitalisation is the principal component of the cost for patient care (70% of the total direct costs), a reduction in HF hospitalisations is an appropriate goal, regardless of which treatment modalities are in place.

SWISS MED WKLY 2002;132:618 622 www.smw.ch 621 Limitations and area of uncertainties In patients with chronic renal insufficiency, the half-life and therefore serum levels of BNP are significantly increased. Therefore, different thresholds need to be defined for this patient population. In our own experience, current cut-off values should only be applied in patients with a serum creatinine below 200 mmol/l. In addition to the bed-site test measuring BNP, a second assay measuring NT-proBNP (Roche) has recently become widely available. Although both test seem to work comparably well, it is important to note their different cut-off values. Data from randomised clinical trials are eagerly awaited and absolutely necessary to establish the role of BNP in different clinical settings. Particularly, its value as an adjunct or alternative to echocardiography will have to be defined. As BNP is considerably less costly, cost-effectiveness analyses are highly desirably. The future for BNP looks promising. Patients with HF despite poly-pharmacotherapy have a tremendous morbidity and mortality exceeding that of most solid organ cancers. Improvement of care and outcome in these patients is definitely needed. BNP testing may be a significant first step. Correspondence: Prof. Peter Buser Kardiologie Universitätsklinik Petersgraben 4 CH-4031 Basel E-Mail: buser@email.ch References 1 McCullough PA, Philbin EF, Spertus JA, et al. Confirmation of a Heart Failure Epidemic: findings from the Resource Utilization Among Congestive Heart Failure (R.E.A.C.H.) Study. J Am Coll Cardiol. 2002; 39:60 9. 2 Yasue H, Yoshimura M, Sumida H, et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 1994;90: 195 203. 3 Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med 1998;339: 321 328. 4 Lerman A, Gibbons RJ, Rodeheffer RJ et al. Circulating N-terminal atrial natriuretic peptide as a marker for symptomless leftventricular dysfunction. Lancet 1993;341:1105 09. 5 Omland T, Aakvaag A, Vik-Mo H. Plasma cardiac natriuretic peptide determination as a screening test for the detection of patients with mild left ventricular impairment. Heart 1996;76: 232 7. 6 Davidson NC, Naas AA, Hanson JK, et al. Comparison of atrial natriuretic peptide B-type natriuretic peptide and N-terminal proatrial natriuretic peptide as indicators of left ventricular systolic dysfunction. Am J Cardiol 1996;77: 828 31. 7 Yamamoto K, Burnett JC Jr, Jougasaki M, et al. Superiority of brain natriuretic peptide as a hormonal marker of ventricular systolic and diastolic dysfunction and ventricular hypertrophy. Hypertension 1996;28: 988 94. 8 McDonagh TA, Robb SD, Murdoch DR, et al. Biochemical detection of left-ventricular systolic dysfunction. Lancet 1998; 351: 9 13. 9 Luchner A, Burnett JC Jr, Jougasaki M, et al. Evaluation of brain natriuretic peptide as marker of left ventricular dysfunction and hypertrophy in the population. J Hypertens 2000;18:1121 8. 10 Krishnaswamy P, Lubien E, Clopton P, et al. Utility of B-natriuretic peptide in identifying patients with left ventricular systolic or diastolic dysfunction. Am J Med 2001;111:274 9. 11 Maisel AS, Koon J, Krishnaswamy P, et al. Utility of B-natriuretic peptide as a rapid, point-of-care test for screening patients undergoing echocardiography to determine left ventricular dysfunction. Am Heart J 2001;141:367 74. 12 Lubien E, DeMaria A, Krishnaswamy P, et al. Utility of B-natriuretic peptide in detecting diastolic dysfunction. Comparison with Doppler velocity recordings. Circulation 2002;105:595 601. 13 Wei CH, Heublein DM, Perella MA et al. Natriuretic peptide system in human heart failure. Circulation 1993;88:1004 49 14 Davis M, Espiner E, Richards G et al. Plasma brain natriuretic peptide in assessment of acute dyspnea. Lancet 1994;343: 440 44. 15 Cowie MR, Struthers AD, Wood DA, et al. Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care. Lancet 1997;350: 1349 53. 16 Dao Q, Krishnaswamy P, Kasanegra R et al. Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting. J Am Coll Cardiol 2001;37:379 85. 17 Cabanes L, Richard-Thiriez B, Fulla Y, et al. Brain natriuretic peptide blood levels in the differential diagnosis of dyspnea. Chest 2001;120:2047 50. 18 Morrison LK, Harrison A, Krishnaswamy P, et al. Utility of a rapid B-natriuretic peptide assay in differentiating congestive heart failure from lung disease in patients presenting with dyspnea. J Am Coll Cardiol 2002;39:202 9. 19 Maisel AS, Krishnaswamy P, Nowak RM et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161. 20 Task Force for the Diagnosis and Treatment of Chronic heart Failure, European Society of Cardiology: W.J. Remme and K. Swedberg. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22:1527 60. 21 Maeda K, Tsutamoto T, Wada A, et al. Plasma brain natriuretic peptide as a biochemical marker of high left ventricular end-diastolic pressure in patients with symptomatic left ventricular dysfunction. Am Heart J 1998;135:825 32. 22 Kazanegra R, Cheng V, Garcia A, et al. A rapid test for B-type natriuretic peptide correlates with falling wedge pressures in patients treated for decompensated heart failure: a pilot study. J Card Fail 2001;7:21 26. 23 Tsutamoto T, Wada A, Maeda K. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure: prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation 1997;96:509 516. 24 Australia-New Zealand Heart Failure Group Richards AM, Doughty R, Nichols MG, et al. Neurohumoral prediction of benefit from carvedilol in ischemic left ventricular dysfunction. Circulation 1999;99: 786 792. 25 Maeda K, Tsutamoto T, Wada A, et al. High levels of plasma brain natriuretic peptide and interleukin-6 after optimized treatment for heart failure are independent risk factors for morbidity and mortality in patients with congestive heart failure. J Am Coll Cardiol 2000;36:1587 93.

B-type natriuretic peptide (BNP): can it improve our management of patients with congestive heart failure? 622 26 Cheng V, Kazanagra R, Garcia A, et al. A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decompensated heart failure: a pilot study. J Am Coll Cardiol 2001;37:386 91. 27 Richards AM, Doughty R, Nicholls MG, et al. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin. Prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction. J Am Coll Cardiol 2001; 37:1781 87. 28 Koglin J, Pehlivanli S, Schwaiblmair M, et al. Role of brain natriuretic peptide in risk stratification of patients with congestive heart failure. J Am Coll Cardiol 2001;38:1934 41. 29 Sodian R, Loebe M, Schmitt C, et al. Decreased plasma concentration of brain natriuretic peptide as a potential indicator of cardiac recovery in patients supported by mechanical circulatory assist systems. J Am Coll Cardiol 2001;38:1942 49. 30 Harrison A, Morrison LK, Krishnaswamy P, et al. B-type natriuretic peptide predicts future cardiac events in patients presenting to the emergency department with dyspnea. Ann Emerg Med 2002;39:131 8. 31 Ishij J, Nomura M, Nakamura Y, et al. Risk stratification using a combination of cardiac troponin T and brain natriuretic peptide in patients hospitalized for worsening chronic heart failure. Am J Cardiol 2002;89:691 5. 32 Nagaya N, Nishikimi T, Okano Y, et al. Plasma brain natriuretic peptide levels increase in proportion to the extent of right ventricular dysfunction in pulmonary hypertension. J Am Coll Cardiol 1998;31:202 8. 33 Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation 2000;102:865 70. 34 Tulevski II, Hirsch A, Sanson BJ, et al. Increased brain natriuretic peptide as a marker for right ventricular dysfunction in acute pulmonary embolism. Thromb Haemost 2001;86: 1193 6. 35 Murdoch DR, McDonagh TA, Byrne J, et al. Titration of vasodilator therapy in chronic heart failure according to plasma brain natriuretic peptide concentration: Randomized compatison of the hemodynamic and neuroendocrine effects of tailored versus empirical therapy. Am Heart J 1999;138:1126 32. 36 Troughton RW, Frampton CM, Yandle T G, et al. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet 2000;355:1126 30. 37 McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clinical judgement in emergency diagnosis of heart failure. Analysis from Breathing Not Properly (BNP) Multinational Study. Circulation 2002;106:416 22. 38 Kuster GM, Tanner H, Printzen G, Suter T M, Mohacsi P, Hess OM. B-type natriuretic peptide for diagnosis and treatment of congestive heart failure. Swiss Med Wkly 2002;132:623 8.

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